Oxalate is a metabolic end product which cannot be broken down by humans. The human body has two main excretory organ pathways for oxalate; the kidney and the intestine. Both pathways are controlled by transporter proteins abundant in the tubular and intestinal epithelium. It is of utmost importance that excretion of oxalate through urine and through the intestinal lumen is sustained.
Primary and Secondary hyperoxaluria are two distinct clinical expressions characterized for example by abnormal excretions of oxalate in the urine. Primary hyperoxaluria is an inherited genetic disorder with defective enzyme activities. In contrast, Secondary hyperoxaluria may be caused by a number of factors including increased dietary ingestion of oxalate or precursors of oxalate, or alterations in intestinal absorption or excretion of oxalate or fat and, alterations in intestinal microbiota or genetic variations of intestinal or tubular oxalate transporter protein expression. Hyperoxaluria is a known complication of Inflammatory Bowel Disease (IBD) and hyperoxaluria with hyperoxalemia is a common consequence of resection of parts of the small intestine and Roux-en-Y gastric bypass surgery. The symptoms of these diseases range from unique kidney stones, recurrent kidney stones and nephrocalcinosis to chronic kidney disease (CKD) and end stage renal disease (ESRD).
Secondary Hyperoxaluria
Oxalate-related CKD due to secondary hyperoxaluria is a health problem throughout the world. It is e.g. characterized by progressively increasing concentrations of oxalate in urine leading to kidney stones.
Secondary hyperoxaluria does normally not lead to ESRD unless hyperoxalemia has occurred. This is mostly common in patients with a resected small bowel such as SBS-patients and bariatric surgery patients.
The liver, the major metabolic organ in the body, is the main site of oxalate production. Oxalate is however not further metabolized and must therefore be excreted. This excretion occurs by two routes; through renal tubular excretion and through intestinal excretion; both excretion routes mediated by active transporter proteins from the SLC26 family. The concentration of oxalate in plasma and hence in tubular fluids is critical, e.g. during renal excretion, where increased oxalate concentrations cause risks for the formation of calcium oxalate crystals in the distal tubules and the connecting duct with subsequent formation of calcium oxalate depositions or calcification of the kidney. The intestinal excretion route is particularly important in preventing pathological conditions that involve elevated plasma oxalate concentrations and calcification of soft tissue.
Secondary hyperoxaluria may be caused by a number of factors including increased dietary ingestion of oxalate or precursors of oxalate, or alterations in intestinal absorption or excretion of oxalate or fat and, alterations in intestinal microbiota or genetic variations of intestinal oxalate transporters. Hyperoxaluria is a known complication of Inflammatory Bowel Disease. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease (Bhasin, 2015). This typically happens in diseases with impaired intestinal excretion due to inflammation such as Inflammatory Bowel Disease, vulvodynia, small intestine bacterial overgrowth (SIBS), gastroenteritis, gastritis, enteritis, enterocolitis, ulcerative colitis, Crohn's disease, and oxalate-related disorder in patients treated with a gastrointestinal lipase inhibitor.
When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in all body fluids and soft tissue. This is mostly common in patients with a resected small bowel such as Short Bowel Syndrome (SBS) patients, some IBD patients, intestinal cancer patients and bariatric surgery patients.
Also ESRD-patients on dialysis tend to build up plasma oxalate as a consequence of the kidney failure and may also suffer from oxalosis that could affect graft survival in kidney transplantation.
Primary Hyperoxaluria
Primary hyperoxaluria (PH) is a paediatric, seriously debilitating and life-threatening genetic disease with a high unmet medical need. PH is a rare autosomal recessive inborn error of glyoxylate metabolism, with significant morbidity and mortality, especially in young children. PH occurs as a consequence of an increased hepatic production of oxalate and is characterised by widespread calcium oxalate crystallization, progressing hyperoxalemia followed by reduced kidney function. As a result of renal oxalate excretion, patients with PH have high levels of urinary oxalate (>0.5 mmol/24 h/1.73 m2 vs. <0.5 mmol/24 h/1.73 m2 in healthy patients) [Hoppe, 2012]. Patients with PH have a wide range of oxalate production, reflected by hyperoxaluria ranging from slightly to highly elevated (>0.5-4.5 mmol/day, 1.73 m2). The extent of oxalate over-production is partly connected to specific genotypes, of which more than 140 are known. Progression to ESRD has been shown to correlate with age at diagnosis (time for exposure to high oxalate), the level of urinary oxalate excretion and kidney function at diagnosis [Zhao et al., 2016]. Patients with a high urinary oxalate excretion and low estimated glomerular filtration rate (eGFR) at diagnosis tend to progress more quickly to ESRD. In PH patients, plasma oxalate gradually increases from 1-3 μmoles/L at early stages to 45-50 μmoles/L at early ESRD. It is common that plasma oxalate rises as high as 150-300 μmoles/L during ESRD and dialysis treatment, leading to systemic accumulation of oxalate and systemic oxalosis.
Often, the first clinical symptoms of PH are renal tubular disorders, manifested by flank pain and kidney stones. The symptoms are primarily caused by calcium oxalate crystal-mediated inflammation of the tubular epithelial cells and growing calcium oxalate crystal deposition gradually causing calcification of the kidney. Progressive renal damage is caused by a combination of tubular toxicity from oxalate, nephrocalcinosis and renal obstruction by stones, or stone removal procedures [Cochat and Rumsby, 2013; Tang et al., 2015]. There is currently no approved pharmaceutical therapy for treatment of PH. Eventually the only curative therapy, only for PH type 1, is a combined kidney and liver transplantation at ESRD (Cochat et al., 2012). Overall, the median renal survival is 24-33 years [Lieske et al., 2005, Harambat et al., 2010].
There are three known types of PH (Type 1, 2 and 3) with Type 1 being the most severe and most widespread (70-80% of known cases) [Hoppe et al., 2009]. The three types of PH are caused by a deficiency or a mislocalisation of different enzymes affecting the hepatic production of oxalate: Type 1 is caused by a deficiency of liver-specific peroxisomal alanine-glyoxylate aminotransferase, Type 2 by a lack of glyoxylate reductase-hydroxypyruvate reductase and Type 3 by a lack of the liver-specific mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase [Cochat and Rumsby 2013, Belostotsky et al., 2010]. The estimated incidence of PH Type 1 is one case per 120,000 live births per year in Europe and the prevalence is one to three per million population [Cochat et al., 1995; Kopp and Leumann, 1995; van Woerden et al., 2003]. Incidence and prevalence may have been underestimated because of underdiagnosis [Leumann and Hoppe, 2001, Hopp et al., 2015].
Declining kidney function results in progressive hyperoxalemia and plasma calcium oxalate supersaturation. The increasing plasma oxalate concentrations cause calcium oxalate deposits to build up in the body. Deposits may be located in the bone, soft tissue, arterial media, peripheral nerves, skin, eyes and the heart [Beck et al., 2013]. Already at early stages in the disease, hyperoxalemia damages cells in the heart, causes calcification (stiffness) and causes inflammation in the myocardium leading to progressive reduced left ventricular strain leading to heart arrhythmia and heart failure (Lagies et al., 2013, Lagies et al., 2014, Lagies et al., 2015).
The interplay between biological molecules and crystal formation is an emerging field of research (see e.g. Aggarwal et al., 2013). In plasma, oxalate may be present as free oxalate, divalent metal-bound free oxalate, protein and lipid-associated oxalate and as solid divalent metal oxalate crystals. The ratio between total oxalate and free oxalate increases with time and disease progression.
After combined liver-kidney transplantation where the new liver produces normal levels of oxalate, an initial decrease of free oxalate is observed. However, when the plasma oxalate concentration is reduced under the saturation limit, calcium oxalate deposits in proteins and lipids, in vessel walls and soft tissue start to dissolve, which results in a new increase of the plasma oxalate concentration. Urinary and plasma oxalate can be elevated for many months to years following transplantation and may lead again to deterioration of the new kidneys (Leumann and Hoppe, 2001). Thus, the prevention of oxalate build-up before and during dialysis and enhancement of excretion of oxalate through the small bowel and through urine is highly beneficial for PH patients. Also for patients with maintained kidney function it is crucial to delay or stop accumulation of calcium oxalate deposition to prevent kidney deterioration.
Secondary Hyperoxaluria with Hyperoxalemia
Gregory et al, 1975, showed that Jejuno-Ileal Bypass (JIB) surgery in otherwise healthy bariatric patients caused renal failure. The elimination of the major intestinal excretion pathway caused high plasma oxalate concentrations, which in turn lead to renal failure. The procedure was discontinued in 1979. Today the dominant procedure for bariatric surgery is Roux-en-Y, a smaller resection of the jejunum/ileum. Although this procedure is associated with recurrent kidney stones, it does not cause ESRD.
Short Bowel Syndrome, SBS, is defined as a disease status where a patient has resected the small bowel and has less than 200 cm bowel left. Similarly to JIB patients, SBS patients have a 45% risk of kidney failure (ESRD) caused by increased concentrations of plasma oxalate.
Zellweger's disease, or the Zellweger spectrum disorders (ZDS) are characterized by a general loss of peroxisomal functions caused by deficient peroxisomal assembly. The disease is heterogeneous in its presentation and survival. Despite a normal level of the enzyme AGT (Alanine:glyoxylate aminotransferase) which is deficient in primary hyperoxaluria, severe hyperoxaluria has been reported in several ZSD patients (van Woerden et al, 2006).
Aspergillus niger infection is a rare fungus infection. A niger is an oxalate producing organism and can cause plasma oxalate at levels that can lead to ESRD.
Oxalobacter formigenes 
Oxalobacter formigenes is a strict anaerobic bacterium that relies exclusively on oxalate as a substrate to obtain energy for its survival and growth. It is currently believed to be the most efficient oxalate-reducing enzymatic system that operates at neutral pH. Not all humans carry populations of O. formigenes in their intestinal tract. For example, there is a low or a complete lack of oxalate-degrading bacteria in the fecal samples of persons who have had jejunoileal bypass surgery. Administration of O. formigenes to a subject in need thereof has been shown to have an effect on dietary oxalate absorption, but it has also been shown to have effect on the elimination of oxalate from plasma to the intestine, promoting the natural intestinal oxalate excretion pathway. O. formigenes has furthermore been shown to promote active elimination of oxalate, possibly through interaction with SLC26 transporter proteins that enhance the oxalate flux from plasma to small bowel (Hatch et al., 2011; Hatch and Freel, 2013).
Compositions comprised of oxalate-degrading bacteria, such as O. formigenes for use in methods for reducing urinary and plasma oxalate for treating oxalate-related conditions have previously been disclosed in the art, such as in U.S. Pat. Nos. 6,200,562, 6,355,242, WO2007075447, and WO2005123114.
There is however still a need for improved compositions for treating oxalate-related disorders, particularly for treating or preventing calcium-oxalate deposition related disorders, such as calcium-oxalate deposition related disorder(s) involving hyperoxalemia as well as treating ESRD patients on dialysis. There is also a need for pharmaceutical compositions that may enhance or increase the excretion of oxalate to reduce the systemic oxalate burden and the related inflammation in patients with calcium oxalate deposition.